An arginine deprivation response pathway is induced in Leishmania during macrophage invasion

Adele Goldman-Pinkovich, Caitlin Balno, Rona Strasser, Michal Zeituni-Molad, Keren Bendelak, Doris Rentsch, Moshe Ephros, Martin Wiese, Armando Jardim, Peter J Myler, Dan Zilberstein

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Abstract

Amino acid sensing is an intracellular function that supports nutrient homeostasis, largely through controlled release of amino acids from lysosomal pools. The intracellular pathogen Leishmania resides and proliferates within human macrophage phagolysosomes. Here we describe a new pathway in Leishmania that specifically senses the extracellular levels of arginine, an amino acid that is essential for the parasite. During infection, the macrophage arginine pool is depleted due to its use to produce metabolites (NO and polyamines) that constitute part of the host defense response and its suppression, respectively. We found that parasites respond to this shortage of arginine by up-regulating expression and activity of the Leishmania arginine transporter (LdAAP3), as well as several other transporters. Our analysis indicates the parasite monitors arginine levels in the environment rather than the intracellular pools. Phosphoproteomics and genetic analysis indicates that the arginine-deprivation response is mediated through a mitogen-activated protein kinase-2-dependent signaling cascade.

Original languageEnglish
Article numbere1005494
Number of pages18
JournalPLOS Pathogens
Volume12
Issue number4
DOIs
Publication statusPublished - 4 Apr 2016

Keywords

  • amino acid sensing
  • Leishmania
  • arginine

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    Goldman-Pinkovich, A., Balno, C., Strasser, R., Zeituni-Molad, M., Bendelak, K., Rentsch, D., Ephros, M., Wiese, M., Jardim, A., Myler, P. J., & Zilberstein, D. (2016). An arginine deprivation response pathway is induced in Leishmania during macrophage invasion. PLOS Pathogens, 12(4), [e1005494]. https://doi.org/10.1371/journal.ppat.1005494